This invention relates generally to compositions and systems for forming crosslinked biomaterials, to the crosslinked biomaterials prepared thereby, and to methods of using such compositions as bioadhesives, for tissue augmentation, in the prevention of surgical adhesions, for coating surfaces of synthetic implants, as drug delivery matrices, for ophthalmic applications, and in other applications, as discussed herein and/or as appreciated by one of ordinary skill in the art.
U.S. Pat. No. 5,162,430, issued Nov. 10, 1992, to Rhee et al., and commonly owned by the assignee of the present invention, discloses collagen-synthetic polymer conjugates prepared by covalently binding collagen to synthetic hydrophilic polymers such as various derivatives of polyethylene glycol.
Commonly owned U.S. Pat. No. 5,324,775, issued Jun. 28, 1994, to Rhee et al., discloses various insert, naturally occurring, biocompatible polymers (such as polysaccharides) covalently bound to synthetic, non-immunogenic, hydrophilic polyethylene glycol polymers.
Commonly owned U.S. Pat. No. 5,328,955, issued Jul. 12, 1994, to Rhee et al., discloses various activated forms of polyethylene glycol and various linkages which can be used to produce collagen-synthetic polymer conjugates having a range of physical and chemical properties.
Commonly owned, copending U.S. application Ser. No. 08/403,358, filed Mar. 14, 1995, a European counterpart of which was published as EP 96102366, discloses a crosslinked biomaterial composition that is prepared using a hydrophobic crosslinking agent, or a mixture of hydrophilic and hydrophobic crosslinking agents. Preferred hydrophobic crosslinking agents include any hydrophobic polymer that contains, or can be chemically derivatized to contain, two or more succiniridyl groups.
Commonly owned, copending U.S. application Ser. No. 08/403,360, filed Mar. 14, 1995, issued Mar. 13, 1996 as U.S. Pat. No. 5,580,923 to Yeung et al., discloses a composition useful in the prevention of surgical adhesions comprising a substrate material and an anti-adhesion binding agent; where the substrate material preferably comprises collagen and the binding agent preferably comprises at least one tissue-reactive functional group and at least one substrate-reactive functional group.
Commonly owned, U.S. application Ser. No. 08/476,825, filed Jun. 7, 1995, issued Mar. 25, 1997 as U.S. Pat. No. 5,614,587 to Rhee et al., discloses bioadhesive compositions comprising collagen crosslinked using a multifunctionally activated synthetic hydrophilic polymer, as well as methods of using such compositions to effect adhesion between a first surface and a second surface, wherein at least one of the first and second surfaces is preferably a native tissue surface.
Japanese patent publication No. 07090241 discloses a composition used for temporary adhesion of a lens material to a support, to mount the material on a machining device, comprising a mixture of polyethylene glycol, having an average molecular weight in the range of 1000-5000, and poly-N-vinylpyrrolidone, having an average molecular weight in the range of 30,000-200,000.
West and Hubbell, Biomaterials (1995) 16:1153-1156, disclose the prevention of post-operative adhesions using a photopolymerized polyethylene glycol-co-lactic acid diacrylate hydrogel and a physically crosslinked polyethylene glycol-co-polypropylene glycol hydrogel, Poloxamer 407(copyright).
Each publication cited above and is incorporated herein by reference to describe and disclose the subject matter for which it is cited.
The invention is directed to a versatile biocompatible composition not previously disclosed or envisioned by those in the biomaterial field. The composition is comprised of a crosslinkable matrix that may be readily crosslinked upon admixture with an aqueous medium to provide a crosslinked composition having a variety of uses, e.g., as a bioadhesive, a drug delivery platform, an implant coating, etc. All components of the composition are biocompatible and nonimmunogenic, and do not leave any toxic, inflammatory or immunogenic reaction products at the site of administration. Preferably, the composition is not subject to enzymatic cleavage by matrix metalloproteinases such as collagenase, and is therefore not readily degradable in vivo. Further, the composition may be readily tailored, in terms of the selection and quantity of each component, to enhance certain properties, e.g., compression strength, swellability, tack, hydrophilicity, optical clarity, and the like.
Accordingly, in one aspect of the invention, a composition is provided that is readily crosslinkable, either in situ or ex situ, to give a biocompatible, nonimmunogenic crosslinked matrix having utility in a host of different contexts, e.g., in bioadhesion, biologically active agent delivery, tissue augmentation, and other applications. The composition is comprised of:
(a) a first crosslinkable component A having m nucleophilic groups, wherein mxe2x89xa72;
(b) a second crosslinkable component B having n electrophilic groups capable of reaction with the m nucleophilic groups to form covalent bonds, wherein nxe2x89xa72 and m+n greater than 4; and
(c) a third crosslinkable component C having at least one functional group selected from (i) nucleophilic groups capable of reacting with the electrophilic groups of component B and (ii) electrophilic groups capable of reacting with the nucleophilic groups of component A,
wherein each of components A, B and C is biocompatible and nonimmunogenic, at least one of components A, B and C is a hydrophilic polymer, and admixture of components A, B and C in an aqueous medium results in crosslinking of the composition to give a biocompatible, noninumunogenic, crosslinked matrix.
Each of the components may be polymeric, in which case at least two components are generally although not necessarily composed of a purely synthetic polymer rather than a naturally occurring or semi-synthetic polymer, wherein xe2x80x9csemi-syntheticxe2x80x9d refers to a chemically modified naturally occurring polymer. Alternatively, one or two of components A, B and C (but not all three) may be a low molecular weight crosslinking agent, typically an agent comprised of a hydrocarbyl moiety containing 2 to 14 carbon atoms and at least two functional groups, i.e., nucleophilic or electrophilic groups, depending on the component. For convenience, the term xe2x80x9cpolynucleophilicxe2x80x9d will be used herein to refer to a compound having two or more nucleophilic moieties, and the term xe2x80x9cpolyelectrophilicxe2x80x9d will be used to refer to a compound having two or more electrophilic moieties.
In another aspect of the invention, a crosslinkable composition is provided that comprises a plurality of biocompatible, non-immunogenic reactive compounds each composed of a molecular core having at least one functional group attached thereto (i.e., through a direct covalent bond or through a linking group), wherein under reaction-enabling conditions each reactive compound is capable of substantially immediate covalent reaction with at least one other of the plurality of reactive compounds by virtue of the at least one functional group. At least two of the reactive compounds contain two or more functional groups to enable crosslinking, and for preparation of highly crosslinked structures, all of the reactive components contain two or more reactive functional groups. Each molecular core is selected from the group consisting of synthetic hydrophilic polymers, naturally occurring hydrophilic polymers, hydrophobic polymers, and C2-C14 hydrocarbyl groups containing zero to 2 heteroatoms selected from N, O, S and combinations thereof, with the proviso that at least one of the molecular cores is a synthetic hydrophilic polymer. Preferably, each molecular core is selected from the group consisting of synthetic hydrophilic polymers and C2-C4 hydrocarbyl groups containing zero to 2 heteroatoms selected from N, O and combinations thereof.
In a related aspect of the invention, a crosslinkable composition is provided that comprises at least three biocompatible, non-immunogenic reactive compounds, wherein a first reactive compound is composed of a synthetic hydrophilic polymer having at least two functional groups attached thereto, a second reactive compound is comprised of a C2-C14 hydrocarbyl group containing zero to 2 heteroatoms selected from N, O, S and combinations thereof, with at least two functional groups attached thereto, and a third reactive compound is comprised of a naturally occurring hydrophilic polymer with at least two functional groups attached thereto. The functional groups of at least one of the reactive compounds are hydroxyl or sulfhydryl groups and the functional groups of at least one other of the reactive compounds are electrophilic groups capable of undergoing reaction with the hydroxyl or sulfhydryl groups to form a covalent bond, such that upon admixture of the composition with an aqueous base, a biocompatible, non-immunogenic crosslinked material is formed.
In another aspect of the invention, a biocompatible, nonimmunogenic, crosslinked matrix is provided by allowing the components of the crosslinkable composition to crosslink under appropriate reaction conditions. As will be discussed in detail infia, suitable reaction conditions involve admixture of all components in an aqueous medium. With certain types of nucleophilic groups, e.g., sulfhydryl and hydroxyl groups, it is preferred that the aqueous medium contain a base, which serves to increase the nucleophilic reactivity of such groups. Preferred bases are generally, although not necessarily, non-nucleophilic.
In other aspects of the invention, methods for preparing and using the aforementioned compositions also provided. Methods of using the compositions encompassed by the present invention include drug delivery methods, use in bioadhesion, delivery of cells and genes, tissue augmentation, prevention of adhesions following surgery or injury, and implant coating. Other methods of use are also within the scope of the invention, as will be described below.